Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by extracellular matrix deposition in lung interstitium. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel activated by physical stimuli and arachidonic acid metabolites. In a recent study, TRPV4-deficient mice did not develop bleomycin-induced lung fibrosis. Pirfenidone is an antifibrotic agent used to treat patients with IPF, although its underlying antifibrotic mechanism is poorly understood. Aims and Objectives: To investigate the effect of TRPV4 blockade by pirfenidone and the role of TRPV4 in lung fibrosis. Methods: We measured the agonist-induced Ca2+ influx of TRPV4 to determine whether its channel activation was inhibited by pirfenidone. A TRPV4 antagonist and pirfenidone were also evaluated in a mouse model of bleomycin-induced lung fibrosis. Arachidonic acid metabolites were determined using a targeted lipidomics approach in fibrotic lung from mice and bronchoalveolar lavage fluid (BALF) from patients with IPF prior to pirfenidone treatment. Results: TRPV4-mediated Ca2+ influx was inhibited by pirfenidone. The TRPV4 antagonist and pirfenidone significantly improved lung fibrosis. Arachidonic acid metabolite levels increased in fibrotic lung and were reduced by pirfenidone. Change in forced vital capacity of patients with IPF treated with pirfenidone significantly correlated with arachidonic acid metabolite levels in BALF (n = 8, r = 0.79, p = 0.02). Conclusions: The antifibrotic action of pirfenidone appears to be partly mediated by TRPV4. Levels of arachidonic acid metabolites in BALF may predict the antifibrotic efficacy of pirfenidone.
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